Oral Isotretinoin and the Use of Conventional Therapy

Dear Editor, We wish to take issue with several points in the recent article that appeared in the Journal of Managed Care Pharmacy (July/August 2002), “Oral Isotretinoin: An Analysis of Its Utilization in a Managed Care Organization.” Of particular concern are the claims of the authors that up to 70% of patients had not received a trial of a topical retinoid before oral isotretinoin therapy, even though the product labeling advises that oral isotretinoin (Accutane) should be used only in patients unresponsive to “conventional therapy.” The authors failed to note that “conventional therapy” as defined in the Accutane U.S. package insert includes systemic antibiotics. Therefore, the failure to note the percentage of patients who had received oral antibiotics (i.e., tetracycline, minocycline, doxycycline, and erythromycin) as a precursor therapy to Accutane is misleading. In fact, data from the Accutane Survey, which was previously conducted by the Slone Epidemiology Center, Boston University School of Public Health, a long-term epidemiologic study, revealed that 93% of all female respondents indicated that they had been on an oral antibiotic previously for their acne (N=36,481), 74% on a topical tretinoin (N=29,078), and 73% on a benzoyl peroxide (N=28,913) (Data on file, covering the time period of January 1, 1995, to June 30, 2002). Further, the authors stated that more than one quarter of patients continued a course of treatment for longer than the 15 to 20 weeks advised in the product labeling. A recent study conducted using national drug c ode health data indicated that the average length of therapy for an Accutane patient is approximately 98.7 days or 14.1 weeks (Roche, data on file, 2002). It should also be noted that Accutane packaging comes in blister packs containing a 10-day supply (10 mg, 20 mg, and 40 mg), so each patient would receive 3 to 6 packs per month. Depending on how the packages were counted, it could lead to a perception on the part of the authors that therapy was “prolonged” when, in fact, the prescriber may be within the recommended dosage of 0.5 mg/kg to 2.0 mg/kg body mass or 120 mg/kg total dose over a course of treatment. The authors report that only 52% of oral isotretinoin prescriptions were written by dermatologists. As the authors presented a limited description of the HMO and its policy and procedures, it is unclear if there is a policy that would limit the number of specialist referrals a nondermatologist could make for dermatologic conditions such as acne. According to the authors, this particular HMO has in place “a prior-authorization policy for topical tazarotene and adapalene, and in patients aged 25 or older (aged 35 in some cases) for topical tretinoin.” This policy appears to be in place to limit prescriptions for topical retinoids used in photo-aging. Nondermatologists unfamiliar with other acne therapies thus may have prescribed isotretinoin inappropriately in the context of an HMO trying to limit use of topical retinoids for photo-aging. The extent of this type of prescribing after denial of topical retinoids could not be determined from the database, as the authors state. A study conducted by IMS indicated that in the years 1995 through 1997, more than 97% of the Accutane prescriptions written for an acne indication were done so by a dermatologist (Roche, data on file). Conclusions of the authors regarding the use of oral isotretinoin without first receiving “conventional therapy” and that oral isotretinoin is being used for a longer period of time than recommended are both inaccurate and misleading.

ducted by IMS indicated that in the years 1995 through 1997, more than 97% of the Accutane prescriptions written for an acne indication were done so by a dermatologist (Roche, data on file).
Conclusions of the authors regarding the use of oral isotretinoin without first receiving "conventional therapy" and that oral isotretinoin is being used for a longer period of time than recommended are both inaccurate and misleading.

The Authors Respond
We would like to respond to a letter that contends that some of the findings from our study published in the Journal of Managed Care Pharmacy (July/August 2002), entitled "Oral Isotretinoin: An Analysis of Its Utilization in a Managed Care Organization," are inaccurate and misleading.
The letter states that our findings regarding the absence of a previous topical retinoid prescription in up to 70% of patients who were prescribed oral isotretinoin does not strongly support the conclusion that the medication is not being used strictly in patients unresponsive to conventional therapy (topical retinoids and/or oral antibiotics), as the product labeling advises. It claims that conventional therapy also includes oral antibiotics, and therefore utilization of this type of therapy prior to the initiation of oral isotretinoin should have been examined. However, although the number (percent) of patients using oral antibiotics for treatment of acne in this study was not delineated separately, this subset was included in the 31% who had prescription medications other than a topical retinoid during the preindex period. The oral antibiotic utilization was purposely not specified separately because of the uncertainty in the actual indications of its use from the database. Also, at least 39% of patients were found to have not received any acne pharmacotherapy, including oral antibiotics, during the 6 months prior to their Accutane prescription. In addition, the designs of the epidemiological studies referenced by the authors of the letter were not explained and, therefore, it could not be determined whether the various cohorts were comparable. For instance, there is the question of how much time elapsed between the end of conventional acne treatment and Accutane initiation in the referenced studies.
The letter also claims that "depending on how the packages (of oral isotretinoin) were counted, it could lead to a perception on the part of the authors that the therapy was prolonged, when, in fact, the prescriber may be within the recommended (guidelines)." The duration of therapy was analyzed using the days supply information submitted by the dispensing pharmacists. Based upon the prescribing physician' s instructions as to dosage and duration of therapy, the correct days supply of www.amcp.org Vol. 9, No. 1 January/February 2003 JMCP Journal of Managed Care Pharmacy 101 Letters Accutane should have been provided to the patient by the pharmacist. As a result, the perception of prolonged therapy is not likely. Furthermore, since the maximum recommended total duration for a course of treatment is 150 days (5 x 30 days) and oral isotretinoin is supplied in 30-day increments, there should not be "extra" dosage dispensed to cover the maximum treatment course. For these reasons, we feel that the days-supply information entered by the pharmacists are accurate and that the issue of "how the packages were counted" does not account for the results presented in the manuscript.
The authors of the letter compared the finding that the average duration of Accutane use was 14.1 weeks to the manuscript' s finding that 27% of patients had received the medication for longer than the recommended duration of therapy. The result of the referenced study, however, does not negate the original finding in the article due to the fact that average duration of therapy may be within the drug' s guidelines while a significant portion of patients still may receive the medication for longer than 20 weeks.
Furthermore, the study investigators mentioned in the manuscript the limitation that prior authorization guidelines in place at this particular managed care organization may confound the finding that only 52% of oral isotretinoin prescriptions were written by dermatologists. It is unlikely, however, that this, in addition to the other limitations mentioned, account for all of the remaining prescriptions written by nondermatologists. Also, it would be reasonable to conclude that had a larger percentage of dermatologists prescribed oral isotretinoin, results would have indicated greater use of conventional therapy prior to Accutane use. This would reflect the specialists' increased experience with and knowledge of this medication and its prescribing guidelines.
The study investigators remain confident in their claims that conventional therapy is not consistently being initiated prior to oral isotretinoin use and also that a significant percentage of patients (27%) who receive Accutane are prescribed a course of therapy that extends beyond the recommended guidelines. The results presented in the article represent utilization patterns from a naturalistic setting and are therefore likely to represent "real world" oral isotretinoin usage.